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CHAPTER22Contents lists available at ScienceDirect

Understanding Modern Vaccines:Perspectives in Vaccinology

Volume 1/Issue 1/25e59

Vaccine immunology

Authors: Oberdan Leo, Anthony Cunningham, Peter L Stern

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Key concepts

n The human immune system consists of two connected compartments e the innate and adaptive e whichfunction via the actions of secreted and cellular effectors

n The innate and adaptive immune systems work sequentially to identify invaders and formulate the mostappropriate response; this interaction is crucially bridged by specialised antigen-presenting cells (APCs)

n The innate response, via the action of APCs, sets the scene for the subsequent adaptive response by providinginformation about the nature of the threat

n Primary exposure to a pathogen or antigen induces the production of a population of adaptive immune cells withantigen specificity that are retained for long periods and provide a rapid response upon subsequent exposure

n The vaccine concept is based on stimulating the body’s defence mechanisms against a specific pathogen toestablish this immunological memory

n Current vaccine strategies take advantage of immunological mechanisms, and often target the innate immunesystem and APCs to induce the desired specific adaptive immune response

n Future research is also set to examine ways of making the immune response more effective in generating crossprotective responses against different subtypes or strains of pathogens exhibiting antigenic variation

2011 Elsevier B.V.

oi:10.1016/j.pervac.2011.05.002

Open access under CC BY-NC-ND license.

www.sciencedirect.com/science/journal/22107622

http://dx.doi.org/10.1016/j.pervac.2011.05.002

http://dx.doi.org/10.1016/j.pervac.2011.05.002

http://creativecommons.org/licenses/by-nc-nd/3.0/

26 UNDERSTANDING MODERN VACCINES

Immunology of vaccines e a brief historyThe science of immunology began in the 19th century. LouisPasteur and Robert Koch established that microorganisms werethe actual cause of infectious diseases, which greatly advancedour understanding of the specific basis of immunity. Pasteurthen disproved the spontaneous generation theory of microbesand Koch developed his four postulates to establish therelationship between the individual agent and the cause ofa disease. The discovery of antibodies in 1890 and the passiveimmunotherapy of diphtheria with anti-diphtheria toxin antibodiesderived from horses resulted in the first Nobel Prize in Medicinebeing awarded to Emil von Behring. In parallel, a greaterunderstanding of the way in which hosts and pathogens interactwas unravelling some of the mysteries surrounding infection anddisease. Host cells that ingested and destroyed invadingmicrobes were identified by Élie Metchnikoff and namedphagocytes (literally ‘eating cells’, from the Greek). Metchnikoffand Paul Ehrlich shared the Nobel Prize in Medicine in 1908 fortheir research in immunology.

The 20th century sawmajor advances in immunology and the relatedfield of vaccinology, and recent studies continue to provide profoundinsights into immunological mechanisms. Figure 2.1 summarisessome of the important immunological milestones that are of particularrelevance to the understanding of vaccinology and indicates severalkey parallel events in vaccine development.Our increased knowledgeof the integrated immune cellular and molecular processes hasfacilitated, often with hindsight, an understanding of the principlesunderpinning effective vaccination. Vaccine design is nowapproached from a more rational, less pathogen-based perspectiveand, increasingly, immunology is guiding vaccine researcherstowards new horizons with the potential to improve on nature. Assuch, the basic concepts of immunology are an essential componentof the foundations of modern vaccinology.

To understand the immunology of vaccines, it is important first toexamine the key players of the immune system (Figure 2.2) and to

Figure 2.1 Immunological milestones of particular relevance to vaccinology. Progress in vaccine design and technology is underpinned

by discoveries in immunology. This is shown by the increasing number of vaccines developed as knowledge of immunity has increased.

HPV, human papillomavirus; Hib, Haemophilus influenzae type b; OPV, oral polio vaccine; IPV, inactivated polio vaccine; Th, T helper

cell; APC, antigen-presenting cell; PRR, pattern recognition receptor; PAMP, pathogen-associated molecular pattern; IL, interleukin;

TCR, T-cell receptor.

VACCINE IMMUNOLOGY 27

understand how they are produced, activated and regulated. In thefollowing section we will discuss the innate and adaptive phases ofthe immune response and how these are bridged by the actions ofspecialised antigen-presenting cells (APCs) e a key step in thesuccessful response to vaccination.

Figure 2.2 Key players of the immune system. The innate

and adaptive immune systems are populated by many

different cells that vary in their roles and responsibilities.

CD, cluster of differentiation.

Although we are continuously exposed to

external antigens, foreign substances

and microorganisms, under normal

circumstances food and airborne

antigens do not provoke the immune

system. In addition, some normal

commensal floras have also co-evolved

with their human hosts to suppress or

avoid triggering defence mechanisms. It

is now known that this is partly because

immune responses are usually only

triggered in the context of threat

or damage to the host; however, both

self and non-self-antigens have the

potential to trigger immune responses

under conditions of acute or

chronic inflammation.


The immune systemPhysical and chemical barriers comprise the body’s first line ofdefence e including the skin, ciliated epithelia, mucous membranes,stomach acids and destructive enzymes in secretions. The immunesystem in vertebrates is a network of cells, tissues and organs thatfunction in a coordinated fashion to defend the body against factorsthat could penetrate its physical and chemical barriers. Some of thekey organs of the immune system are illustrated in Figure 2.3, andinclude the primary lymphoid organs (bone marrow and thymus)where lymphocytes are generated, and the secondary lymphoidorgans (peripheral lymph nodes, spleen, tonsils, Peyer’s patches)where immune responses are initiated and regulated.

INNATE AND ADAPTIVE IMMUNITY

All organisms have some form of innate protection against theoutside world, which may be as simple as a cell wall or waxy

Figure 2.3 Organs and tissues of the immune system. The innate immune system is formed from a combination of physical barriers (skin,

mucus), chemical defences (acids, antimicrobial peptides) and specialised cells capable of responding to pathogens without needing to

recognise specific antigens (A). The adaptive immune system consists of a network of primary and secondary organs, where immune cells are

either produced or reside until they become activated (B).



coating. As higher organisms evolved, their innate defencesbecame more sophisticated and the jawed vertebratesdeveloped a highly specialised system of immunity e acquired(or adaptive) immunity e which may have evolved asa consequence of co-evolution with specialised parasites,increased metabolic rates due to dietary changes, and genomicinstability. Jawed vertebrates thus have two interlinked systemswhich act sequentially to establish protective immunity e theinnate immune system and the adaptive immune system. Theinnate immune system acts as a first line of defence whichcomprises both cellular and non-cellular effectors. This systemprovides early containment and defence during the lag timebefore adaptive immune effectors are available. Innate immunitycomprises both soluble (eg complement, lysozyme) and cellulareffectors (eg natural killer [NK] cells, macrophages and dendriticcells [DCs]). The innate and adaptive immune systems areprincipally bridged by the action of specialised APCs, whichtranslate and transfer information from the body tissues andinnate immune system to the adaptive immune system, allowinga systemic response to a localised threat. The innate immunesystem therefore drives and shapes the development of adaptiveimmune responses via chemical and molecular signals deliveredby APCs to induce the most appropriate type of adaptiveresponse. The adaptive immune system forms the second,antigen-specific line of defence, which is activated andexpanded in response to these signals.

The innate immune systemCELLS OF THE INNATE IMMUNE SYSTEM

Cells of the innate immune system are produced in the bonemarrow and then migrate to different anatomical locations. Theinnate immune cell repertoire includes tissue-resident cells such asmacrophages and immature DCs, and cells which circulate viablood and the lymphatic system, such as monocytes, neutrophils,eosinophils, NK cells and innate T cells. Non-immune system cells


at vulnerable locations, including keratinocytes and other epithelialand mucus-producing cells, fibroblasts and endothelial cells, canalso exhibit innate defensive behaviours.

DETECTION OF PATHOGENS

Invading pathogens are detected by the innate immune systemthrough molecular-sensing surveillance mechanisms. Thesemechanisms include detection of pathogens via patternrecognition receptors (PRRs), expressed by cells of the innateimmune system, which can be secreted, or expressed on thecell surface, or are present in intracellular compartments (egDNA/RNA sensors). Examples of PRRs are the transmembraneToll-like receptors (TLRs) and Table 2.1 lists the qualities ofseveral TLRs. The model system in Figure 2.4 illustrates thelocation of the main human PRRs, and highlights the signallingpathways of several mammalian TLRs.

The key feature of cells of the innate immune system is their ability todirectly recognise different classes of pathogens e eg viruses andbacteria e by PRRs. These receptors are able to bind to molecules(such as bacterial membrane components) that are sharedby several pathogens (eg all Gram-negative bacteria expresslipopolysaccharide [LPS]), enabling the innate immune system tosense the occurrence of an infectious event. Recently, DCs andmacrophages have been shown to react to signals released bydamaged cells, indicating that the innate immune system canreact to both the presence of infectious microbes (viapathogen-associated molecular patterns [PAMPs]) and to theconsequences of an infectious event.

Epithelial cells, fibroblasts and vascular endothelial cells are alsoable to recognise PAMPs, and signal to innate immune cells wheninfected, stressed or damaged. This is mediated by stress signals(such as heat-shock proteins) and active small-molecule peptides(such as defensins, lysozymes and cathelicidins) which havedirect antimicrobial properties and also act to alert immune cells.Specialised chemical messengers, including cytokines and

TABLE 2.1. EXAMPLES OF MAMMALIAN TLRS

Receptor Pathogen/ligand Location

TLR1 Bacteria

Parasites

Cell surface

TLR2 Bacteria

Fungi

Viruses

Parasites

Cell surface

TLR3 Viruses Cell compartment

TLR4 Bacteria

Viruses

Parasites

Cell surface

TLR5 Bacterial flagellin Cell surface

TLR6 Mycoplasma Cell surface

TLR7 Bacteria Cell compartment

TLR8 Single-stranded DNA Cell compartment

TLR9 Pathogen CpG DNA Cell compartment

This table provides examples only and is not intended to be an exhaustive list. CpG, adjacent cytosine (C) and guanine (G) residues in a

linear sequence connected by a phosphodiester bond (see Chapter 4 e Vaccine adjuvants, Figure 4.9).

The local reactogenicity observed

followingvaccinationprobablyreflects the

inductionof local inflammatoryresponses,

which are important in the initiation of a

successful immune response.


chemokines, are secreted by stressed/damaged cells and innateimmune cells to attract other resident and circulating innate cells tothe site of infection. Cells dying due to infection also release othersmall molecules, such as urea, which alert DCs.

Appendices, Supplementary Table 1 shows some examples ofthe innate biological consequences of signalling through PRRs.The downstream adaptive responses triggered by these signalsare determined by the intracellular signalling pathway into whichthe signal feeds. Further fine-tuning of these responses to specificoutcomes is believed to be achieved via the recruitment ofspecific intracellular adaptor molecules, which modify andmanipulate the signal sent to the nucleus of the innate cell to tailorthe profile of gene expression. Redundancy exists in pathogendetection systems, as multiple receptors may recognise the samepathogenic structure and, conversely, a single receptor may be

Figure 2.4 Cell-surface and intracellular PRRs. TLRs are a class of pathogen receptors that are known to recognise many PAMPs including

surface antigens and/or a pathogen’s genetic material (A). For example, TLR4 is positioned at the cell surface and recognises bacterial and

viral antigens, whereas TLR9 is located intracellularly and recognises bacterial and viral DNA. Transmission of the signal is mediated by

intracellular adaptor molecules (B). Activation of these messengers triggers the movement of transcription factors to the nucleus, where

proinflammatory gene expression is induced or enhanced. There are many opportunities in the signalling pathways for the cell to recognise

a PAMP and become responsive, maximising the chances of pathogen detection.

PAMP, pathogen-associated molecular pattern; LPS, lipopolysaccharide; TLR, Toll-like receptor; DS, double stranded; SS, single stranded;

CpG, adjacent cytosine (C) and guanine (G) residues in a linear sequence connected by a phosphodiester bond.


The inflammatory responseThe local inflammatory response aims to

rapidly recruit innate effector cells to an

infected or damaged body site. The local,

elevated secretion of cytokines and

chemokines causes an increase in blood

vessel permeability and the release of

plasma, producing the swelling, redness,

pain and heat that are typical symptoms

of inflammation. Inflammation is also a

protective response that helps to initiate

the healing process. Soluble factors

produced during an innate response can

damage healthy cells; inflammation

therefore needs to be a closely

regulated process.


capable of delivering more than one signal to the host cell.Overall, the integration of these signals by APCs leads to theiractivation. This enables them to act as messengers to preciselydefine the nature of the perceived danger and convey thisinformation to the secondary lymphoid organs, where theyinteract with, and specifically activate, the relevant adaptiveimmune response.

EFFECTORS OF THE INNATE RESPONSE

Under some circumstances, pathogen clearance may be achievedby innate immune effectors without activation of an adaptiveimmune response. Activated innate cells act as phagocytes,engulfing and destroying the pathogen within intracellular vesiclescontaining digestive enzymes. To be efficient, this responserequires both the recruitment and activation of phagocytes at thesite of infection, a process often referred to as the inflammatoryresponse. Cells residing in proximity to the infection site areactivated upon recognition of PAMPs, and secrete a large arrayof soluble mediators, including chemokines and cytokines(Figure 2.5). Chemokines behave as chemoattractants (Appendices,Supplementary Table 2), favouring the recruitment of innate immunecells to the site of infection, while cytokines (including tumour necrosisfactor and interferons) (Appendices, Supplementary Table 5) act byincreasing the phagocytic activity of cells. Innate immune cells alsoproduce a series of soluble chemical factors (such as peptides) thatare able to directly target the invading microbes.

Additionally, antigens are taken up by innate cells, with immatureDCs the most specialised among them. The antigen is subsequentlyprocessed and the DC differentiates into an APC. Antigen-carryingAPCs then migrate to the draining lymph node and provide the linkbetween the innate and adaptive immune responses.

Complement

The complement system consists of approximately 25 proteins thatwork together to ‘complement’ the action of the adaptive immune

Figure 2.5 Innate effector mechanisms. The innate immune system responds to challenge by secreting factors that directly kill or inhibit the

invader; or that attract more cells capable of removing the threat and, if necessary, alerting the adaptive immune system. Tissue-resident

cells, such as macrophages, secrete antimicrobial factors in response to proinflammatory stimuli. Circulating cells are recruited to the site by

chemotactic stimuli, released by damaged or infected epithelial and endothelial cells and other innate immune cells. If innate effectors

contain and remove the invader, infection can be resolved without the intervention of the adaptive immune response. Additionally, antigens

are taken up by immature DCs. The antigens are processed intracellularly and the cell transforms into an APC followed by migration to the

draining lymph node.

DC, dendritic cell; APC, antigen-presenting cell.


The diversity of adaptiveimmune receptorsIn contrast to innate cells which express

a few dozen pathogen-specific receptors,

lymphocytes can express an enormous

diversity of antigen-specific receptors

(around several thousand billion),

a number that far exceeds the total

number of genes present in our genome

(around 25,000). Antigen receptors are in

fact encoded by a set of ‘mini-genes’ that

undergo complex recombination events,

allowing the generation of diverse

proteins from a limited number of building

blocks. Additional individual changes and

random insertions in the genes further

increase the diversity of the receptors.

The vast T- and B-cell repertoires that

humans possess provide a massive

potential for antigen-specific responses.

This repertoire is maintained with single

or very fewcells expressing receptors that

will recognise any given antigen, until

individual clonesare selectively expanded

in response to a specific challenge.

Notwithstanding these abilities of the

adaptive immune system, rare individuals

may have a genetic makeup that does not

enable them to react to one or other

antigen present on a pathogen.


response in destroying bacteria. Complement proteins circulate inthe blood in an inactive form. Once activated, complementcomponents serve several effector roles including the recruitmentof phagocytes, the opsonisation of pathogens to promotephagocytosis, the removal of antibodyeantigen complexes and thelysis of antibody-coated cells.

The adaptive immune systemOne critical function of the innate immune system is to alertthe adaptive immune response, whereby lymphocytes withantigen-specific receptors are activated and proliferate to fight thepathogenic threat. Their antigen receptors evolved in response tothe selection pressure of different pathogens and therefore havevery diverse characteristics.

Lymphocytes can be found circulating in the blood/lymph andresiding within secondary lymphoid organs, such as the lymphnodes and spleen. There are two main subsets of lymphocytesinvolved in adaptive immune responses, whose nomenclaturereflects the site of their development e B cells develop in the bonemarrow and T cells develop in the thymus.

The adaptive immune system essentially functions via the productionof three key types of effector: antibodies (produced from B cells),cytokines and cytolytic molecules (produced by Tcells) (Figure 2.6).

THE FACILITATORS AND EFFECTORS OF THE ADAPTIVEIMMUNE RESPONSE

Facilitators: the role of the APC

The first cells to interact with an incoming pathogen are often thephagocytes of the innate immune system, which can engulf anddegrade pathogens. However, it is now clearly recognised thatprofessional APCs, typified by DCs, can ingest pathogen-derivedproteins, partially digest, process and transport the peptideproducts to the cell surface, rather than targeting them forcomplete destruction.

Figure 2.6 Adaptive immune effectors. Adaptive immune effectors are recruited to the site of challenge and also circulate systemically to deal with

any disseminated pathogens/antigens. Adaptive effectors can act by interacting directly with the pathogen, or by modulating the action of innate

immune effectors. CD4þ cells often represent the first lymphocyte subset activated during an adaptive immune response and are able to affect the

behaviour of other immune cells (thereby acting as ‘helpers’). Soluble antibodies reaching the site of infection perform effector functions such as

enhancing phagocytosis (greater detail on antibody effector functions is provided in Figure 2.7). CD4þ T cells expressing a Th1-type phenotype

activate macrophages locally via secretion of proinflammatory cytokines, increasing their phagocytic and antimicrobial activity. CD8þ T cells

recruited to the site of infection/inflammation express surface molecules that are directly cytotoxic to infected target cells via apoptosis but can

also exert antiviral activity on these cells via cytokines.

CD, cluster of differentiation; CTL, cytotoxic T lymphocyte; Th, T helper cell.


MHC restriction andT-cell subsetsMHC molecules display antigenic

peptides to Tcells. MHC class I molecules

receive endogenous proteins, including

those derived from intracellular

pathogens, and are expressed by virtually

all nucleated cells of the body.MHCclass I

peptides are recognised by the T-cell

receptor (TCR) expressed by CD8D Tcells.

MHC class II molecules are usually

expressed by a restricted set of cells such

as macrophages, DCs and B cells. They

present peptides derived from exogenous

antigens, taken up via mechanisms such

as endocytosis and phagocytosis.

Antigenic peptides presented by MHC

class II molecules are bound by TCRs

expressed by CD4D T cells.


These pathogen-derived peptide antigens are bound bya specialised set of receptors known as human leukocyte antigens(HLA) that act as ‘antigen-presenting’ molecules. These moleculesare encoded by a gene family called the major histocompatibilitycomplex (MHC). DCs displaying pathogen-derived antigen on thecell surface are also endowed with migratory properties that allowthem to leave the infected site and migrate towards the nearestlymph node. DCs therefore represent an important cellularmessenger, able to transport molecular pathogen fragments tosecondary lymphoid organs. Antigen fragments displayed by DCsare destined to activate pathogen-specific T cells residing in thelymph nodes.

Facilitators: T-cell activation

T cells represent a subset of lymphocytes that differentiate withinthe thymus, a small bi-lobular organ situated in the anteriormediastinum. Each T cell expresses a unique antigen-specificreceptor (the TCR) with a unique recognition capacity.

T cells do not directly recognise whole pathogens, but are onlyspecifically activated by DCs transformed into APCs which presentmolecular fragments (mostly peptides derived from limiteddigestion of protein antigens) in association with MHC moleculesat the cell surface. Naïve lymphocytes are therefore ‘blind’ to livemicroorganisms and need the help of APCs to adequately react toan invading pathogen.

Facilitators: CD4D T cells

An individual naïve Tcell can only be activated by a protein antigenfor which it has a specific receptor, and which has been processedand presented by an APC. Cells activated by antigen-bearing DCsexpress the cluster of differentiation (CD)4 cell-surface protein, andare thus referred to as CD4þ Tcells. These cells often represent thefirst lymphocyte subset activated during an adaptive immuneresponse, and play both modulatory and effector roles during animmune response. CD4þ cells act primarily by secreting solublefactors (cytokines) that are able to exert direct antimicrobial

Identified around 2005, Tfh cells were

thought to be part of the Th2 subset

based on the profile of cytokines they

produced, but have subsequently been

identified as a distinct subset of T cells

that fulfil some of the roles originally

attributed to Th2 cells.


properties and affect the behaviour of other immune cells. In mostcases, CD4þ cells help other immune cells perform their task andare, therefore, referred to as helper Tcells (Th). Based on the typesof cytokines they secrete and differing abilities to help other subsetsof immune cells, several sub-populations of Th cells have beenidentified (Appendices, Supplementary Table 3).

One subset of Th cells, the Th1 cells, appear to secrete mainlyinterferon-gamma (IFNg), a cytokine known to limit pathogen survivaland spreading. It is also known to promote the differentiation ofcytolytic cells that are able to destroy cells infected with intracellularpathogens (see CD8þ T cells). Th1 cells are, therefore, consideredimportant for inducing immune responses involved in the clearanceof pathogens.

Another subset of T helper cells, the Th2 cells, produce cytokines(interleukins [IL] IL-4, IL-5, IL-13) that appear particularly apt atactivating innate cells (eosinophils, mast cells) which are ofteninvolved in the immune response to large extracellular parasites.

Another subset, termed follicular T helper cells (Tfh) based on theirtissue localisation in follicular structures, have been defined bysecretion of IL-21, a cytokine thought to favour the secretion ofantibodies by antigen-specific B cells.

Activation of CD4þ cells represents a key step in setting inmotion an adaptive immune response. Through their abilityto secrete cytokines, these helper cells will augment the capacityof other immune cells to perform their tasks. The adaptiveimmune response is frequently characterised by two effectorcell populations, the CD8-expressing cytolytic T cells and theantibody-secreting B cells.

Adaptive effectors: CD8D T cells

CD8þ T cells exploit the TCR/MHC interaction aroundpathogen-derived peptides to detect and fight intracellularpathogens. To achieve this, CD8þ Tcells rely on the fact that virtuallyall nucleated cells (with a few notable exceptions) present fragmentsof intracellular proteins at their surface as part of the body’s normal


surveillance processes. In contrast to classically defined APCs, whichdisplay antigenic fragments in association with MHC class IImolecules, non-immune cells use a closely related set ofmolecules todisplay peptides derived from the cytoplasm e the MHC class Imolecules. This complex mechanism of antigen presentation allowsCD8þ Tcells to scan proteins fromwithin the cell, while preserving theintegrity of the cell membrane.

The salient feature of CD8þ Tcells is their ability to secrete cytotoxicfactors in addition to cytokines. These factors enable CD8þ T cellsto kill cells displaying pathogen-derived peptides presented byMHC class I molecules, for example a virus-infected cell. By killingcells expressing high levels of virus-derived peptides at theirsurface, CD8þ cells are able to eliminate infected cells before thecompletion of a viral replication cycle, thus limiting viral spreadwithin an infected individual. In addition, CD8þ Tcells can inhibit viralreplication without destroying the target cells by producingcytokines that are able to interfere with pathogen replication.

CD8þ cytolytic cells can also eliminate cells displaying abnormalhost peptides, such as those presented by tumour cells, andtherefore play an important role in the immune control of aberrantcell growth. Although CD8þ T cells can directly react to cellsexpressing the appropriate antigen/MHC class I complexes, theiroptimal activation programme (proliferation and acquisition of fullcytolytic potential) is best achieved in the presence of cytokinesproduced by type 1 CD4þ T helper cells.

B cells and antibodies

Antibodies represent a highly diverse set of soluble proteinssecreted by the subset of lymphocytes referred to as B cells. B cellsdevelop in the bone marrow before undergoing a process ofdifferentiation and maturation in the spleen. As with T lymphocytes,each B lymphocyte expresses a unique antigen receptor (B-cellreceptor [BCR]) enabling the cells to react to a specific antigen. Inmarked contrast to TCRs, BCRs can directly bind to moleculesexpressed by pathogens, with no need for previous internalisation

Antibodies play multiple roles in the

control and elimination of pathogens,

and in the response to vaccination.

Binding of targets by antibodies is often

sufficient to initiate processes that

render the pathogen harmless.


and presentation by APCs or other innate immune cells. Uponantigen encounter, B cells expressing the cognate BCR are inducedto proliferate and differentiate into plasma cells, which can secretelarge amounts of a soluble form of the BCR that we know as anantibody. This soluble protein is thus released in the blood and otherbody fluids (referred to as the ‘humors’) enabling them to fightinfection at distant sites.

Antibodies can be viewed as bifunctional molecules, able to bothrecognise and eliminate a given antigen or pathogen. Antibodymolecules consist of a ‘constant’ fragment, a structural featurecommon to all antibodies of a given isotype, and a ‘variable’region, which includes the portion that gives the antigenspecificity (or antigen-binding characteristics) of the antibody.The variable region of the antibody can exist in a huge numberof molecular configurations, and an individual’s BCR repertoire isgenerated to maximise capability to produce antibodies that areuseful against diverse potential pathogenic threats. The constantpart of the molecule exists in five different forms (isotypes)(immunoglobulin [Ig] A, IgD, IgE, IgG and IgM, see Appendices,Supplementary Table 4) that determine the ability of an antibodyclass to localise to particular body sites and target specific typesof infection, and to recruit the optimal local effector cells (seeFigure 2.7).

B cells can differentiate into antibody-secreting cells uponencounter with a given antigen or pathogen. In most cases,direct activation of B cells by an antigen is observed in responseto repetitive antigenic structures, such as carbohydrates foundin bacterial walls. These T cell-independent responses arecharacterised by the secretion of low-affinity antibodies of theIgM type. This type of response is often stereotyped in nature,lacking the typical memory response upon re-exposure to thesame antigen (see section titled Immunological memory).

In most cases, optimal B-cell activation and differentiation intoantibody-secreting plasma cells is only observed when both Band T cells are simultaneously activated by the same pathogen.

Figure 2.7 Effector functions of antibodies. Antibodies play multiple roles in the control and elimination of pathogens and in the response to

vaccination. Antibodies can bind directly to the surface of pathogens (1) or soluble mediators (2) preventing infection of host cells and

neutralising pathogen-derived toxins. Antibodies can recruit effector molecules such as complement (3) or activate effector cells via their Fc

portion (4, 5). Binding of the Fc region of an antibody to a specific Fc receptor expressed by innate cells can facilitate pathogen internalisation

and destruction by phagocytes (by a process referred to as ‘opsonisation’) (4). Similarly, ligation of Fc receptors on granulocytes promotes

their degranulation and triggers potent antimicrobial responses including the removal of antibodyeantigen complexes and the lysis of

antibody-coated cells (5).

Fab, fragment antigen binding; Fc, fragment, crystallisable.


In these instances, CD4þ T cells differentiate into Tfh cells thatare able to provide a helper signal to B cells. T cell-dependentB cell responses are characterised by the secretion ofhigh-affinity antibodies and a large spectrum of isotypes (inparticular IgG), and are typically associated with immunityresulting from natural exposure.


THE ROLE OF CYTOKINES

Cytokines are small proteins secreted by activated innate andadaptive immune cells (such as DCs, macrophages and T cells),which direct the activity of other cells to coordinate an appropriateimmune response. Cytokines are a diverse family of moleculeswhich include interleukins, interferons and growth factor responses(Appendices, Supplementary Table 5). Cytokines may act in anautocrine, paracrine or endocrine fashion, by binding cell-surfacereceptors and stimulating signalling pathways, ultimately affectingthe gene expression of the target cell. Cytokines are referred to aseither proinflammatory or anti-inflammatory, depending on their roleduring the establishment of immune responses. These two typesthen act together to control and regulate different aspects of theimmune response.

Agenetic deficiencyof Treg cells results in

severe autoimmune syndrome;

conversely, infection may be established

where responses are inappropriately

suppressed by selective activation of Treg

cells, for example by the stomach

pathogen Helicobacter pylori. Over-

suppression of immune responses by

regulatory mechanisms may also result

in an inadequate response to vaccination

in some individuals.

REGULATORY T CELLS

Immune responses are prevented, down-regulated or terminated bymultiple mechanisms. These mechanisms include clonal deletion,the activity of suppressor monocytes and anti-inflammatorycytokines, induction of apoptosis, induction of unresponsivenessby resting APCs, expression of inhibitory cell-surface co-receptorsand the activity of regulatory CD4þ T cells.

Regulatory Tcells (Treg cells) belong to the CD4þ T-cell subset. Theirrole is to inhibit immune or inflammatory responses by blocking theactivity of effector T cells, helper T cells and APCs. They are key tothe down-regulation of immune responses at the appropriate pointfollowing a protective response, the immunological toleranceprocess (avoiding immune response towards self-antigens andnon-threatening antigens, eg from food and commensal floras),and prevention of uncontrolled or chronic inflammatory responses.

Antibodies produced during the immune response may alsodown-regulate subsequent immune responses, for example byelimination or masking of antigen, hence limiting the activation ofadditional T cells. Antibodyeantigen complexes may also bind toinhibitory receptors, initiating suppressive responses.


IMMUNOLOGICAL MEMORY

Upon differentiation, naïve Tand B cells, each expressing a uniqueTCR and BCR, migrate to the blood and peripheral lymphoidorgans. Due to the large number of possible immune receptors,lymphocytes expressing a given antigen specificity will be tooinfrequent to mount an effective immune response on their own.Thus, upon antigen encounter, T and B lymphocytes must undergorapid proliferation, leading to the accumulation of an increasednumber of cells expressing receptors for the incoming antigen.Some of these cells will differentiate into effector cells (such ascytokine-producing T cells or antibody-secreting plasma cells),while others will become ‘memory cells’, able to survive for a longperiod of time within the host.

Exposure to an antigen (pathogen or vaccine) therefore leads toa long-term (and sometimes permanent) modification of thecellular repertoire, such that the relative frequency of T and B cellsspecific for an individual antigen is increased in antigen-exposedindividuals compared with naïve individuals (Figure 2.8). Inaddition to their increased frequency, memory T and Blymphocytes also display novel functional properties, enablingthem to develop secondary (recall) responses on re-encounterwith their specific antigen, or a closely related antigen. Theadaptive response on secondary exposure leads to a rapidexpansion and differentiation of memory T and B cells intoeffector cells, and the production of high levels of antibodies.A higher proportion of IgG and other isotypes of antibodiescompared with the level of IgM characterises memoryantibody responses.

By definition, all effective vaccines lead to the development ofimmune memory, by mimicking the threat of an infection andproviding antigens derived from the specific pathogen. Theability to generate immune memory is the key attribute of theadaptive immune system, which is crucial for the long-termprotection of individuals and populations. Generating immunememory depends on a high degree of interaction among many

Figure 2.8 The kinetics of primary and recall (memory) immune responses. On first exposure to a pathogen or antigen (referred to as ‘priming’ in

vaccination), the innate immune system must detect, process and translate the threat into a form that can be understood by the adaptive immune

system. This occurs via the bridging actions of APCs and takes days/weeks. Following resolution of the challenge, a specialised ‘memory’ cell

population remains. The cells within this population are maintained for a long time (months/years) and may remain within the host for the rest

of their host’s life. On subsequent exposure to the same antigen (referred to as ‘boosting’ in vaccination), the innate immune response is

triggered as before but now the memory cell populations are able to mount a greater and more rapid response as they do not need to

undergo the same activation process as naïve cells.

APC, antigen-presenting cell; IgM, immunoglobulin M; IgG, immunoglobulin G.



different cell types, which maintains higher numbers of T and Bcells that were selected as the most useful in the primaryimmune response. However, while the relative contribution ofclonal memory cells to protection can be inferred from themolecules they express and their functional behaviour, thepresence of memory cells per se is not indicative of absoluteprotection against disease.

There are several theories as to how new effector cells aregenerated from memory cells when needed, and it is likely that allof these mechanisms play a role in immunological protection.One possibility is that short-lived effector cells are producedcontinuously by memory cell division, replacing the older cells ofthe same specificity e this process would be driven by thepersistence of antigen. Long-lived effector cells may also begenerated from memory cells in a process driven by cytokinesand engagement of PRRs in response to a new encounter withthe pathogen. A third possibility is that effector cells remain forlong periods in specialised survival niches e there is someevidence that this is an important mechanism in B-cell memory,since depletion of memory B cells does not significantly impactthe level of circulating antibodies, probably due to the presence oflong-lived plasma cells.

Summary of differences between theinnate and adaptive immune systemsAs we have seen, the innate and adaptive immune systems occupydistinct evolutionary and functional niches. The innate immunesystem, along with physical and chemical barriers, provides a firstline of defence against invasion or damage. A system of cellular andsoluble mediators then transmits the nature of the threat to theadaptive immune system, which selectively expands the appropriaterepertoire in order to deal with the threat. The key differencesbetween these two systems are summarised in Table 2.2. In thenext section, the mechanisms linking innate and adaptive immunitywill be discussed.

TABLE 2.2. KEY DIFFERENCES BETWEEN INNATE AND ADAPTIVE IMMUNITY

Innate immunity Adaptive immunity

First line of defence against pathogens Second line of defence against pathogens

Acts rapidly (hours/days), vital to triggering of adaptive responses Relatively slow to develop (days/weeks)

Triggered by threat/damage Triggered by exposure to specific antigen

Activated by microbial general patterns and damage Very focused, targets a specific pathogen

Acts through pathogen class-specific mechanisms of

neutralisation/control

Acts through antigen-specific and non-specific effectors

No recall response on subsequent exposure to same threat Rapid recall response on subsequent exposure to same antigen

(immunological memory)

Initiates processes of tissue repair


Innate and adaptive immune responsesare bridged by the actions of APCsAs previously discussed, the innate immune system provides anessential link between the first encounter with a pathogen at the siteof infection and the eventual establishment of immune memory.Innate cells (such as macrophages and DCs) are strategicallylocated at body sites with a high risk of infection (such as epitheliaand mucosal surfaces). These types of cells act as both a first line ofdefence against danger and as key messengers that are able toalert the adaptive immune system. Since naïve Tand B cells are notpre-positioned in most organs and tissues of the body, they rely onthe innate immune system to sense an infectious event.

Among tissue-resident cells, the most efficient APCs are DCs.Immature DCs which have captured antigen become activatedand mature into functional APCs, while migrating to the regionaldraining lymph node or submucosal lymphoid tissue. Mature DCsexpress high levels of antigen/MHC complexes at the cell surfaceand undergo morphological changes, which render them highlyspecialised, to activate naïve Tcells. When they arrive in the lymphnode, DCs present processed antigen and express co-stimulatorysignals. The signals provided by DCs promote T-cell differentiationand proliferation, initiating the adaptive T cell-mediated immune


response. APC activation is therefore a necessary prerequisite foran efficient adaptive immune response.

DCs not only provide antigen and co-stimulation to naïve T cells,but also contribute to the initial commitment of naïve T helper cellsinto Th1, Th2 or other subsets. This directs the efficient induction ofT helper cells with appropriate cytokine profiles early duringinfections, without the need for direct contact betweenantigen-specific T cells and pathogens.

Undigested pathogen-derived antigens are also drained by thelymph and transported to the B cell-rich area of the lymph node,where they are exposed to BCR-expressing cells. An adaptiveimmune response is therefore initiated in a draining lymph node bythe concerted action of innate immune cells and free antigens.These activate Tand B lymphocytes, respectively, to proliferate anddifferentiate into effector and memory cells.

The type of communication employed by the immune systemrepresents a unique approach to multi-system signalling andcommunication over distances. As well as employing thesoluble mediators e proinflammatory messengers, chemokinesand soluble danger signals e the immune system usesmigratory APCs to physically transport messages from theperiphery to the induction sites of adaptive immune response,eg in lymph nodes.

Notably, by selectively migrating in response to infectious/cell-damaging events, DCs act as filters for the adaptive immuneresponse, helping T and B cells to ignore innocuous foreignantigens. Thus, the innate immune response plays an important rolein selecting antigens that represent a real threat to the organism thatrequires an adequate adaptive response.

The immune response e summaryThe response to pathogens in humans takes place over a largeanatomical distance and in distinct phases, which are summarisedin Figure 2.9.

Figure 2.9 An overview of the human immune response. The innate immune response is initiated (1). Innate immune cells begin to mature and

differentiate, while migrating to the lymph nodes (2). APCs induce the adaptive immune response including activation of T cells into effector cells

and differentiation of T cells into memory cells (3e5). Naïve B cells differentiate into antibody-secreting plasma cells and memory B cells following

activation by helper CD4þ T cells (6) and activated CD4þ T cells activate tissue-resident macrophages (7). Antibodies can enhance the effector

functions of innate cells (8) and also neutralise pathogens directly (9). Cytotoxic T cells can directly kill infected tissue/cells via molecular and

chemical signalling (10) and also induce infected cells/phagocytes to kill intracellular pathogens, or inhibit pathogen replication (11). Not all

T cell subsets are represented in this illustration.

APC, antigen-presenting cell; CD, cluster of differentiation.



The innate immune response is initiated at the site of challengewhen a foreign entity triggers a defensive response, which ismediated by chemical signals. These signals attract respondinginnate immune cells (monocytes, DCs etc) which travel to the siteand engulf fragments of the pathogen. The monocytes and DCsthen leave the site via lymphatic vessels and begin to mature anddifferentiate, while travelling to the local draining lymph nodes.Differentiation gives rise to APCs that interact with naïve Tcells at thelymph nodes and bear receptors for the antigenic peptidesexpressed on the surface of the APC. Molecular, antigenic andcytokine signals combine to direct the differentiation and activationof CD4þ T cells into distinct effector subtypes. This is the inductionphase of the adaptive immune response.

A sub-population of CD4þ T cells differentiates into memory cells,which are capable of responding rapidly on repeat exposure to thesame antigen. CD8þ T cells also receive antigenic and cytokinestimulation from APCs and undergo differentiation either intomemory-type cells or armed effector cytotoxic cells. Activatedhelper CD4þ Tcells interact with antigen-bearing naïve B cells and,via molecular and cytokine signals, direct their activation intoi) antibody-secreting plasma cells, and ii) memory populations thatpersist for long periods. Activated CD4þ Tcells also travel to the siteof infection and, via cytokine signals, activate tissue-residentmacrophages to become fully active and to destroyphagocytosed antigen/pathogens.

Antibodies can enhance the effector functions of innate cells, forexample, by enhancing phagocytosis. Soluble antibodies at the siteof challenge can neutralise pathogens directly by binding to theirsurface. Cytotoxic T cells can directly kill infected tissue/cells viamolecular and chemical signalling. These cells can also induceinfected cells/phagocytes to kill intracellular pathogens, or caninhibit pathogen replication via chemical and molecular signals.

On secondary exposure to the same antigen or pathogen, specificadaptive effectors with a memory phenotype can rapidly proliferateand produce a new wave of adaptive immunity at the site of


challenge. This pathway can occur independently of further innateimmune events and is the basis of vaccination.

The coordination of all these phases ensures that a call for help fromthe periphery is relayed to the regional secondary lymphoid tissuesand that appropriate effectors are directed to the site of infection bya series of chemical and molecular signals. This cycle of an immuneresponse forms the basis for the principles of vaccination(Figure 2.10) and is discussed further in the next section.

Figure 2.10 The flow of information following

intramuscular vaccination. An antigen

delivered by a vaccine is taken up by

macrophages and immature APCs (1). APCs

migrate to the lymph node draining the site of

vaccination (2). The adaptive immune response

is now initiated and effectors, such as CD4þ

effector T cells, cytotoxic T cells and soluble

antibodies (3), are produced which travel

throughout the bloodstream and back to the

site of vaccination.

APC, antigen-presenting cell.


Modern immunology appliedto vaccinologyThe modern immunology concepts described in this chapter areof great importance both for the design of new vaccines and to helpus understand why vaccines do e or do not e work as efficientlyas desired.

IMMUNOLOGICAL REQUIREMENTS OF A VACCINE

Identification and selection of the most appropriate antigen

Vaccines aim to prevent the disease symptoms that are theconsequences of a pathogenic infection. In most cases, this doesnot occur by completely preventing infection but by limitingthe consequences of the infection. As discussed earlier, anunderstanding of the disease pathogenesis and natural immunecontrol is, therefore, very useful when selecting appropriateantigens upon which to base a vaccine.

Vaccines developed from pathogens can vary in the complexity ofthe pathogen-derived material they contain. Our understanding offundamental immunology, as well as the selection techniques used,has resulted in new vaccines that are better characterised than everbefore, and has also initiated a more rational approach to vaccinedesign. The different approaches to antigen selection arediscussed in depth in Chapter 3 e Vaccine antigens.

Induction of innate immune responses

The immune system is triggered by a combination of events andstimuli, as described previously. The requirement for more than thepresence of a ‘foreign’ antigen to elicit an immune response musttherefore always be considered in vaccine design, particularly whenusing highly purified or refined antigens (see Chapter 3 e Vaccineantigens). Highly refined subunit antigen formulations, and someinactivated whole pathogens, do not contain many of the molecularfeatures and defensive triggers that are required to alert the innateimmune system. These types of antigen are designed to minimise


excessive inflammatory responses but, as a result, may besuboptimally immunogenic. Under these circumstances, theaddition of adjuvants (see Chapter 4 e Vaccine adjuvants) canmimic the missing innate triggers, restoring the balance betweennecessary defensive responses and acceptable tolerability.

Induction of CD4D T cell help

The induction of CD4þ Tcells is essentially controlled by the natureof this initial inflammatory response. Therefore, vaccine adjuvantscan play a role in guiding how CD4þ T cells are induced and howthey further differentiate and influence the quality and quantity of theadaptive immune response.

Selection and targeting of effector cells

It is important to recognise that the dominant immune response toa given pathogen or antigen may not necessarily be the optimumresponse for inducing protection; indeed through evolution somepathogens have developed strategies to evade or subvert theimmune response, as is the case with Neisseria gonorrhoeae, wherethe dominant antibody response actually facilitates infection bypreventing complement-dependent bactericidal activity. Antibodytitres are often considered to represent adequate indicators ofimmune protection but, as discussed above, may not be the actualmechanism by which optimal protection is achieved. Useful specificso-called immune correlates of immunity/protectionmay be unknownor incompletely characterised. Therefore, modern vaccine design stilllooks to clinical trials to provide information about clinical efficacyand, if possible, the immunological profiles of protected individuals.Immunogenicity is assessed by laboratory measurement of immuneeffectors, typically antibodies. Increasingly, however, specific T-cellactivation is included in the parameters assessed, as adequate T-cellimmunity may be essential for recovery from some infections andimproved assay techniques have allowed these evaluations tobecome more standardised and offer more robust data. This canthen open the door to understanding observed clinical efficacy(or lack of) and to defining at least some of the features of


vaccine-induced protection. By preferentially targeting the bestimmunological effectors, vaccines can then hope to mimic orimprove on nature’s own response to infection.

VACCINE DEVELOPMENT CHALLENGES

Immune correlates of protection e what, whenand where?

Successful natural immune responses can be measured inprotected individuals and assessed in terms of, for example, theproduction of specific types of antibody or a particular pattern ofcytokine expression by T cells e this gives the correlates ofprotection, which can then be reproduced using a vaccine.Correlates of protection can only be determined from a clinical trialwhere protection from disease or infection is determined in cohortsof vaccinated versus unvaccinated individuals.

The majority of vaccines developed so far have been assessed bytheir ability to elicit antibody responses. One example where this iswell defined is rubella, where protective antibody titres can bereliably assessed to determine whether an individual is protectedpost-vaccination. However, immune correlates of protection are notwell defined in many diseases, including human immunodeficiencyvirus (HIV) where the presence of antibodies is not a correlate ofimmunity/protection, since infected individuals develop antibodieswithout being protected against disease. This is a significant barrierto HIV vaccine research and reflects the generation of variants of thevirus which evade serological effectors such as antibodies. There isevidence that some highly exposed individuals can developresistance to HIV infection, suggesting that immunity and, therefore,a vaccine are possible. However, the complex immunologicalprofiles of these rare individuals make it difficult to define theprotective effectors and their immunological triggers.

Historically, the generation of antibodies has been the main goal ofvaccination; however, for future vaccines this may be insufficient orinappropriate. Thus, developments are focused on the generationof specific CD4þ (Th1) lymphocyte or CD8þ cytotoxic T cell


responses. These are approaches under investigation for herpessimplex virus (HSV) and tuberculosis vaccines, where selectedT-cell determinants delivered as recombinant proteins or via live viralvectors aim to target the CD4þ and CD8þ T-cell compartments.

The need to guide the immune response towards protectivemechanisms has been demonstrated in trials of respiratorysyncytial virus (RSV) vaccines, where exposure of vaccinees tonatural RSV infection led to severe pulmonary pathologycharacterised by infiltration of mononuclear cells and eosinophils,suggesting a strongly Th2-biased response. This resulted inhospitalisations and deaths of at least two young children followinga study in the 1960s. Hence, insufficient knowledge of the factorsaffecting natural control of an infection or the inability to balance theintegrated immune response induced by a vaccine can affect theability to produce a safe, effective vaccine.

Hostepathogen interactions in vaccine immunology

Vaccine immunology is greatly affected by the complex interactionsthat occur between the host and the pathogen. These interactionscan determine the type of immune response a vaccine needs toinduce to offer protection against an actual challenge. Manypathogens have complex life cycles and sophisticated strategieswhich allow them to be successful in their pathological niche. Thismay be as simple as a waxy coating which makes opsonisationmore difficult, or as complex as the ability to modulate host geneexpression and manipulate or change the molecular signalsdisplayed by infected cells. Examples of the immunologicalchallenges posed by some pathogens are discussed below.

Bacteria

Mycobacterium tuberculosis is a good example of a bacterialpathogen with several defensive mechanisms. These include anunusual waxy coating which facilitates survival once the bacteriumis taken up into APCs e this is particularly effective as it allows thebacterium to escape from degradation within macrophages,


establishing an immunologically ‘silent’ refuge. In addition,M. tuberculosis is able to down-regulate the expression ofantibacterial immune effectors, such as nitric oxide, by infectedmacrophages. The intestinal Gram-negative pathogen Salmonellaenterica is able to modify its LPS into a form that is less identifiableby TLR4. Impairment of the LPS/TLR4 interaction reduces earlyactivation of the innate immune response and hence allowsSalmonella to better survive and proliferate within the host’sintestinal cells.

Viruses

Viruses such as cytomegalovirus (CMV) also have highly evolvedhost avoidance strategies. This member of the herpesvirus familyhas evolved multiple genes for the manipulation of host immunity,including those whose products prevent the display of viral proteinsin association with MHC class I molecules (hence avoidingtriggering or being targets of specific CD8þ cytotoxic T cells) byboth diverting viral products out of the degradation pathway and bysuppressing expression of MHC class I molecules. Ordinarily, thiswould attract the attention of NK cells, which are activated bynucleated cells lacking surface expression of MHC class Imolecules. However, CMV possesses genes encoding MHC class Imimics, which are expressed on the surface of infected cells andare able to bind to receptors which switch off the cytotoxic activity ofcirculating NK cells.

Parasites

Parasites present a challenge to vaccine design because theparasite life cycle comprises distinct phases within a single host,during which it will reside in different anatomical locations and, mostimportantly, express different surface antigens. Thus, parasitesrepresent an immunological ‘moving target’. In addition, the immuneresponse to parasites is very complex and may be modulated by theparasite itself, and hosteparasite interactions are often poorlydefined. There are currently no available vaccines for parasitic


diseases of humans, although one vaccine for malaria is currently inPhase III clinical trials (see Chapter 6 e Vaccines of the future).

IMMUNOLOGICAL IMPEDIMENTS TO EFFECTIVEVACCINATION e TOLERANCE

Other important considerations in vaccine immunology include thephenomena of immune tolerance and immunological/antigenicinterference, which can suppress or prevent development of adequateimmune responses following vaccination. Immune tolerance refers tothe induction of immunological non-responsiveness by repeatedexposure to similar antigens, such as polysaccharide antigens; thiseffect is dose-dependent and may be limited in time as increasingthe interval between subsequent doses can partially restoreresponsiveness. Immunological/antigenic interference occurswhen previous or concomitant exposure to another antigenprevents the development of adequate responses to the vaccineantigen, which may be due to previous or concurrent vaccinations.Another potential cause of reduced vaccine efficiency is thepresence of passively induced immunity, eg that transferred frommother to foetus, where the vaccine antigen is neutralised bypre-existing maternally-derived antibody without triggeringa host-derived immune response in the infant. These phenomenacan be avoided, however, by taking them into account inimmunisation schedules.

Live viral vaccines may cause immuno-

logical interference with each other if

administered at the wrong intervals e for

example, live varicella virus vaccines and

the measles, mumps and rubella vaccine

should be given at the same time or 1

month apart to avoid interference.

Modern vaccines e interactions withthe immune systemVaccines developed within the last decade have benefited from anincreased knowledge of the innate and adaptive immune responses,and are better characterised in terms of their immunologicalmechanism of action than many of their predecessors. It hasbecome apparent that the most successful vaccines mimic infectionby actively targeting the innate phase of the immune response andmodulating or enhancing the interface bridged by APCs. Theimmune response to a vaccine can be substantially improved


through the use of adjuvants, which stimulate the innate immuneresponse by providing elements that are normally present in mostpathogens but absent from a highly purified antigen. The vaccineswhich we know most about tend to be those that include anadjuvant, as the effects of these compounds on the innate immunesystem and the downstream adaptive response can be studiedboth in isolation and in combination with antigen. There are severalpoints during the innate response at which adjuvanted vaccinesare known or believed to influence the subsequent adaptiveimmune response, thereby initiating a long-lasting immuneresponse. This includes modulating or mimicking the interactionbetween PAMPs and innate receptors such as TLRs; influencingor promoting intracellular signalling pathways; enhancingantigen uptake by APCs; and up-regulating or modifyingcell-surface crosstalk between APCs and naïve T cells. Someexamples of specific adjuvanted vaccines that exert directeffects on the innate immune response are discussed inChapter 4 e Vaccine adjuvants.

We are increasingly able to understand the balance betweenmechanisms of immune activation and immune regulation. Inparallel, the detailed assessment of the immunological mechanismof action of vaccines helps us to achieve effective immunestimulation without inducing a chronic inflammatory state. Thisinformation also helps us to reassess the role of vaccines andnatural infections as potential triggers of autoimmune diseases.

Recently, much effort has been devoted to the design of vaccinesthat induce CD8þ Tcell responses, as they have a central role in thehost response to viral infections and cancers. However, as yet, it isnot easy to measure the CD8þ T cell response in humans ina consistent and reliable way; this will remain the focus of researchin the coming years.

ConclusionAdvancing knowledge of the immunological mechanisms of actionof existing vaccines provides essential information that is vital to the


production of new, well-tolerated, effective vaccines. Howimmunological requirements are balanced with the complexities ofthe pathogen, the needs of the target vaccinees, the practicalities ofantigen production, and the stability and tolerability of the eventualvaccine represents a constantly evolving challenge. The factorsaffecting the selection and production of different types of antigensare discussed in Chapter 3 e Vaccine antigens.

FURTHER READINGS

Appay V, Douek DC, Price DA. CD8D Tcell efficacy in vaccination and disease. Nat Med2008;14:623e628

Castilow EM, Olson MR, Varga SM. Understanding respiratory syncytial virus (RSV)vaccine-enhanced disease. Immunol Res 2007;39:225e239

Janeway CA, Travers P, Walport M et al. Immunobiology: the Immune System in Healthand Disease. 5th ed. New York: Current Biology Publications; 2004

Jenkins KA, Mansell A. TIR-containing adaptors in Toll-like receptor signalling. Cytokine2010;49:237e244

Kao JY, Zhang M, Miller MJ et al. Helicobacter pylori immune escape is mediated bydendritic cell-induced Treg skewing and Th17 suppression in mice. Gastroenterology2010;138:1046e1054

Kindt J, Goldsby RA, Osborne BA. Kuby Immunology. 6th ed. New York: W H Freemanand Company; 2007

Siegrist CA. Vaccine immunology. In Plotkin SA, Orenstein WA, Offit PA (eds). Vaccines.5th ed. New York: Saunders Elsevier; 2008 p 17e36

INTERNET RESOURCES

British Society for Immunology. Available at: http://www.immunology.org/ Date accessed:12 Aug 2010

http://www.immunology.org/

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